Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 17; p. 127390
• Main Authors: Liu, Jian, Guiadeen, Deodial, Krikorian, Arto, Gao, Xiaolei, Wang, James, Babu Boga, Sobhana, Alhassan, Abdul-Basit, Yu, Wensheng, Selyutin, Oleg, Yu, Younong, Anand, Rajan, Xu, Jiayi, Kelly, Joseph, Duffy, Joseph L., Liu, Shilan, Yang, Chundao, Wu, Hao, Cai, Jiaqiang, Bennett, Chad, Maloney, Kevin M., Tyagarajan, Sriram, Gao, Ying-Duo, Fischmann, Thierry O., Presland, Jeremy, Mansueto, My, Xu, Zangwei, Leccese, Erica, Zhang-Hoover, Jie, Knemeyer, Ian, Garlisi, Charles G., Stivers, Peter, Brandish, Philip E., Hicks, Alexandra, Kim, Ronald, Kozlowski, Joseph A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2020; Elsevier
• Subjects: Bruton’s Tyrosine Kinase; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Kinase selectivity; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Rat CIA model; Science & Technology; Structure based drug design; X-ray crystal structure; Rat CIA model; Bruton’s Tyrosine Kinase; X-ray crystal structure; Structure based drug design; Kinase selectivity; Bruton's Tyrosine Kinase; TYROSINE KINASE INHIBITOR; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127390

[Display omitted] Bruton’s tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.